Therapeutically useful cysteinol and homocysteinol derivatives

ABSTRACT

Compounds of the formula   &lt;IMAGE&gt;   (in which n is equal to 0 or represents a whole number from 1 to 10 and m represents the number 1 or 2) and their pharmacologically acceptable salts are prepared and have therapeutic, in particular hypolipemic, activity.

This invention relates to bis-alkylene cysteinols and bis-alkylene homocysteinols, a process for their preparation and their use as therapeutically active substances, notably with hypolipemic activity, the compounds being in the form of their base or pharmacologically acceptable salt.

The compounds according to the invention correspond to the general formula I ##STR2## in which n is equal to 0 or represents a whole number from 1 to 10 and m represents the number 1 or 2.

The compounds of formula I (in which n represents a whole number from 1 to 10) may be prepared by reaction of an alkane dihalide of formula II

    x--(ch.sub.2).sub.n --X                                    (II)

(in which X represents a halogen atom and n represents a whole number between 1 and 10) with S-benzylcysteinol or S-benzylhomocysteinol of the respective formulae IIIa and IIIb ##STR3## in liquid ammonia in the presence of an alkaline amide, such as sodium amide. The dihalide of formula II can be used pure or in solution in a solvent such as diethyl ether; it may be used in stoichiometric proportion or in excess, for an example an excess amounting up to 100%. Preferably in the dihalide X represents a bromine atom.

The separation of the reaction products may be effected in known fashion: evaporation of the ammonia, extraction of the organic phase and purifications.

If necessary or desired the product obtained may be converted into a pharmacologically acceptable salt in known manner.

Compounds of formula I in which n equals O may be prepared by conversion of the S-benzyl derivatives of formula IIIa or IIIb into a thiol and then oxidation with air to obtain the corresponding disulphide.

The S-benzyl derivatives are suitably converted into the thiol in liquid ammonia in the presence of sodium amide. The thiol obtained may suitably be oxidized by bubbling air into an aqueous solution of the thiol in the presence of ferric chloride.

The invention provides a pharmaceutical composition comprising, as active ingredient, a compound of formula I or a pharmacologically acceptable salt thereof together with a pharmacologically acceptable carrier or diluent. The compounds of formula I are used in pharmaceutically acceptable purity, with a pharmaceutically acceptable carrier or diluent selected generally from the group consisting of solid extenders, ingestible containers of capsules and cachets, non-solvent liquid media, solvent liquid media comprising a solvent and at least one additive selected from the group consisting of sweetening, flavouring, colouring, preserving and surface active agents, and sterile liquid media.

Preferably the composition is in an orally administrable form, most preferably a form permitting administration of doses of from 5 to 30 mg/kg per day.

The invention further provides a method of treating a human patient which method comprises administering to the patient a compound of formula I or a pharmacologically acceptable salt thereof.

S-benzylcysteinol of formula IIIa used as a starting material, may be obtained in the following fashion in three stages:

(1) Preparation of S-benzylcysteine according to the method described by M. D. Armstrong, Journal of Organic Chemistry, 16, 749-53 (1951).

(2) Preparation of the hydrochloride and the ethyl ester base of S-benzylcysteine according to J. C. Crawall, D. F. Elliot and K. C. Hooper, Journal of the Chemical Society, 4066-68 (1956).

(3) Preparation of S-benzylcysteinol by reductive saponification in the presence of lithium aluminium hydride or triethyllithium borohydride; this compound has been obtained in impure form in the form of the oxalate by J. C. Crawall, same reference as above.

S-benzylhomocysteinol of formula IIIb can be prepared according to analogous stages to those described above. The first, that is the preparation of the S-benzylcysteine, is described in Biochemical Preparations 5, 87.

The following Examples 1 to 14 illustrate the preparation of particular compounds of the invention. Examples A and B illustrate the preparation of starting materials.

EXAMPLE A S-benzylcysteinol ##STR4##

In a three necked 2000 ml. flask provided with a sealed mechanical stirrer, a coolant with calcium chloride protection, and a bromine ampoule protected from atmospheric humidity there are placed:

350 ml of rectified anhydrous ether on LiAlH₄,

15.8 g of LiAlH₄ (i.e. four times the theoretical quantity which is half a mole of LiAlH₄ per mole of the ester).

The suspension is brought to reflux with stirring. The solution of the base ester (50.3g) in anhydrous ether is introduced at a suitable speed to maintain the reflux.

The boiling of the reaction mixture is continued for 10 minutes after the end of the addition of the solution of the ester base.

After cooling, the excess of lithium aluminium hydride is destroyed by the minimum quantity of water added drop by drop.

The alumina is removed and washed with ether.

The ethereal solutions are distilled. The residue crystallises.

29.5 g of white crystals are obtained.

Yield: 71.2%--Melting Point: 38° to 40° (Tottoli).

    ______________________________________                                          Analysis for C.sub.10 H.sub.15 O N S = 197.29                                 ______________________________________                                         C%    calculated  60.87    found   61.19 to 61.27                              H     "            7.66    found    7.81 to  7.80                              N     "            7.09    "        7.01 to  7.01                              S     "           16.25    "       16.16                                       ______________________________________                                    

The S-benzylcysteinol may be purified by distillation.

B.Pt. 142° to 144° C. under 0.25 mm mercury.

Melting point: 44° (Tottoli).

    ______________________________________                                          Analysis for C.sub.10 H.sub.15 O N S = 197.29                                 ______________________________________                                         C%      calculated  60.87    found   60.78                                     H       "            7.66    "        7.98                                     N       "            7.09    "        7.10                                     S       "           16.25    "       16.51                                     ______________________________________                                    

IR SPECTRUM: NH₂ band at 1600 cm⁻¹ ; CH₂ OH band at 1050 cm⁻¹.

    ______________________________________                                         NMR SPECTRUM: Reference Tetramethylsilane (TMS)                                CH.sub.2S       2.5 p.p. m (m)                                                  ##STR5##       2.9 p.p. m (m)                                                 HOCH.sub.2      3.48 p.p. m (m)                                                SCH.sub.2Cl     3.67 p.p. m (s)                                                 ##STR6##       7.3 p.p. m (s)                                                 T.L.C.                                                                               (Thin layer chromatography using                                               silica gel prepared plates                                                     60F254, Ex. Merck; H = 8 cm)                                             Solvent:                                                                               Propanol      60                                                               NH.sub.4 OH   30                                                               Ethylene Diamine                                                                             10                                                       Developer:                                                                             ninhydrin-I.sub.2.                                                     ______________________________________                                    

example b s-benzylhomocysteinol (a) Ethyl 2-amino-4-benzylthiobutanoate ##STR7##

300 g of S-benzylhomocysteine are placed in suspension with stirring in 3,900 liters of absolute ethanol. The reaction mixture is refluxed for 5 hours in the presence of a rapid current of dry HCl.

The solution is decolourised by carbon black and the filtrate reduced to dryness. The composition taken up in 1200 ml of ether and 135 g of triethylamine is stirred for 1 hour at the laboratory temperature. Insolubles are washed by diethyl ether with stirring. The ethereal filtrates are mixed and reduced to dryness.

The residue, 315.4 g, is a yellow oil which is rectified under 0.8 mm Hg.

Boiling Point: 170° to 178° C.

Yield 71.5% ((226.2g).

    ______________________________________                                         Analysis for C.sub.13 H.sub.19 O.sub.2 NS = 253.36                             ______________________________________                                         C%     calculated 61.63    found   61.66 to 61.72                              H      "          7.56     "        7.83                                       N      "          5.53     "        5.72 to 5.81                               S      "          12.66    "       12.59                                       ______________________________________                                    

IR SPECTRUM: NH₂ band: 1.580 cm⁻¹ ; COOR band: 1.748 cm⁻¹.

    ______________________________________                                                T.L.C. (Prepared silica gel plates 60F254;                                         H = 8 cm)                                                           ______________________________________                                                Butanol          40                                                            Acetic Acid      10                                                            Ethylene Diamine 50                                                            Developers:ninhydrin -                                                                          I.sub.2                                                ______________________________________                                    

Hydrochloride (Purified in ethanol/diethyl ether).

Melting Point: 62.5° to 63.5° (Tottoli).

    ______________________________________                                         Analysis for C.sub.13 H.sub.20 O.sub.2 NSCl = 289.82                           ______________________________________                                          C%    calculated 53.87   found    53.79                                                                               to 53.78                               H      "          6.95    "        7.09                                        N      "          4.83    "        4.84 to 4.88                                S      "          11.06   "        11.02                                       NMR SPECTRUM - Reference TMS                                                    ##STR8##                                                                      ______________________________________                                    

(b) S-benzylhomocysteinol ##STR9##

To a suspension of 43 g of LiAlH₄ (4 times the theoretical amount) in 1000 ml of anhydrous ether brought to reflux under mechanical agitation, there is added a solution of 144 g of the ethyl ester of the S-benzylhomocysteine in 600 ml of anhydrous ether at a speed such that the reaction mixture continues to boil. After the end of the addition, refluxing is continued for 1 hour.

The excess of LiAlH₄ is destroyed by water.

After extraction and washing with diethyl ether, the ethereal solutions are reduced to dryness. The residue is rectified under reduced pressure at 170° to 180° C. under 0.6 mm Hg.

A colourless oil crystallising in an ice-box was collected.

Yield 73% (88 g)-- Melting point: 31° to 32° C. (Tottoli).

    ______________________________________                                         Analysis for C.sub.11 H.sub.17 O N S = 211.32                                  ______________________________________                                         C%     calculated   62.52    found    62.34                                    H      "            8.11     "        8.37                                     N      "            6.63     "        6.74                                     S      "            15.17    "        15.00                                    ______________________________________                                    

IR SPECTRUM: NH₂ band: 1585 cm⁻¹ ; OH band: 1053 cm⁻¹ .

    ______________________________________                                         NMR SPECTRUM-Reference TMS                                                     Aromatics       7.4 p.p.m. (s)                                                  ##STR10##      3.7 p.p.m. (s)                                                 SCH.sub.2CH.sub.2                                                                              2.5 p.p.m. (m)                                                  ##STR11##      3 p.p.m. (massive)                                             CH.sub.2 OH     3.4 p.p.m. (massive)                                           T.L.C.:                                                                              Silica gel prepared plates                                                     60F254; H = 8 cm                                                         Propanol   60                                                                  NH.sub.4 OH                                                                               30                                                                  Ethylene Diamine                                                                          10                                                                  Developers: ninhydrin - I.sub.2                                                ______________________________________                                    

example 1 2,8-diamino-4,6-dithia-1,9-nonanediol (Djenkolol) ##STR12##

500 ml of liquefied ammonia are placed in a 1000 ml flask with three necks provided with a sealed mechanical stirrer, a potash seal and bromine ampoule. 12 g of S-benzylcysteinol are added and little by little 2.8 g (the theoretical mount) of sodium cut in to fine flakes. There is then introduced drop by drop 6.2 g dibromomethane (20% excess relative to the theoretical quantity of 5.2g). The blockage of the --SH grouping is practically instantaneous (sodium nitroprussiate test).

The excess amide is destroyed by the theoretical quantity of ammonium chloride. The ammonia is evaporated at the laboratory temperature under a weak nitrogen current. The residue is dried under vacuum and extracted three times with 200 ml of THF. The extracts are decolourised on carbon black and evaporated to dryness.

The residue is recrystallised in ethyl acetate.

Practical Yield: 58.8% (4.0 g)

Melting point: 82° to 84° (Tottoli)

The compound is soluble in the cold in water, alcohol, ether.

    ______________________________________                                         Analysis for C.sub.7 H.sub.18 O.sub.2 N.sub.2 S.sub.2 = 226.35                 ______________________________________                                         C%    calculated  37.14   found   37.25 to 37.26                               H     "           8.01    "       8.10                                         N     "           12.37   "       12.53 to 12.56                               S     "           28.33   "       28.35                                        ______________________________________                                    

IR SPECTRUM: NH₂ band: 1600 cm⁻¹ ; OH band: 1050 cm⁻¹ .

    ______________________________________                                         NMR SPECTRUM Reference TMS                                                     SCH.sub.2S      3.9 p.p.m. (s)                                                 CH.sub.2 OH     3.6 p.p.m. (m)                                                  ##STR13##                                                                     T.L.C.                                                                               Prepared silica gel plates 60F254;                                             H = 8 cm                                                                 Propanol   60                                                                  NH.sub.4 OH                                                                               30                                                                  Ethylene Diamine                                                                          10                                                                  Developers: ninhydrin - I.sub.2                                                ______________________________________                                    

example 2 2,11-diamino-4,9-dithia-1,12-dodecanediol ##STR14##

The operational procedures described in Example 1 are used using 1,4-dibromo-butane in place of dibromomethane. The product obtained is extracted with ether and recrystallised in ethyl acetate.

Yield: 25% -- Melting Point: 78° to 80° (Tottoli) While crystals soluble in water, alcohols, ether.

    ______________________________________                                         Analysis for C.sub.10 H.sub.24 O.sub.2 N.sub.2 S.sub.2 = 268.44                ______________________________________                                         C%      calculated                                                                               44.74     found   44.89                                      H       "         9.01      "       9.27                                       N       "         10.43     "       10.18                                      S       "         23.88     "       23.97                                      ______________________________________                                    

IR SPECTRUM: NH₂ band at 1600 cm⁻¹ ; OH bands at 1050 cm⁻¹ and 1350 cm⁻¹ .

    ______________________________________                                         NMR SPECTRUM - Reference TMS                                                   CH.sub.2OH      3.6 p.p.m. (m)                                                  ##STR15##      3 p.p.m. (m)                                                   S(CH.sub.2).sub.4S                                                                             2.6 p.p.m. (m)                                                 CH.sub.2CH.sub.2                                                                               1.7 p.p.m. (m)                                                 T.L.C.                                                                               Prepared silica gel plates 60F254;                                             H = 8 cm                                                                 Propanol   60                                                                  NH.sub.4 OH                                                                               30                                                                  Ethylene Diamine                                                                          10                                                                  Developers: ninhydrin - I.sub.2                                                ______________________________________                                    

example 3 2,13-diamino-4,11-dithia-1,14-tetradecanediol ##STR16##

The operational method described in Example 1 is used using 1,6-dibromo-hexane in place of dibromomethane. The product obtained is extracted with benzene and recrystallised in ethyl acetate.

Yield: 63% -- Melting Point: 83° to 84° (Tottoli) White crystals soluble in water, alcohols, ether.

    ______________________________________                                         Analysis for C.sub.12 H.sub.28 O.sub.2 N.sub.2 S.sub.2                         ______________________________________                                         C%      caculated 48.61     found   48.91                                      H       "         9.52      "       9.71                                       N       "         9.44      "       10.67                                      S       "         21.63     "       21.78                                      ______________________________________                                    

IR SPECTRUM: NH₂ band at 1600 cm⁻¹ ; CH₂ OH bands at 1050 cm⁻¹ and 1350 cm⁻¹ .

    ______________________________________                                         NMR SPECTRUM - Reference TMS                                                   CH.sub.2 OH     3.5 p.p.m. (m)                                                  ##STR17##      2.9 p.p.m. (m)                                                 CH.sub.2SCH.sub.2                                                                              2.6 p.p.m. (m)                                                 (CH.sub.2).sub.4                                                                               1.5 p.p.m. (m)                                                 T.L.C.                                                                               Prepared silica gel plates 60F254;                                             H = 8 cm                                                                 Propanol   60                                                                  NH.sub.4 OH                                                                               30                                                                  Ethylene Diamine                                                                          10                                                                  Developers: ninhydrin - I.sub.2                                                ______________________________________                                    

example 4 2,15-diamino-4,13-dithia-1,16-hexadecanediol ##STR18##

The operational method described in Example 1 is used using 1,8-dibromo-octane in place of dibromomethane. The product obtained is extracted with benzene, then recrystallised first in ethyl acetate and then in dichloro-methane.

Yield: 50% -- Melting Point: 92° to 94° (Tottoli) White Crystals soluble in water, alcohols, ether.

    ______________________________________                                         Analysis for C.sub.14 H.sub.32 O.sub.2 N.sub.2 S.sub.2 = 324.54                ______________________________________                                         C%      calculated                                                                               51.81     found   51.97                                      H       "         9.93      "       10.23                                      N       "         8.63      "       8.77                                       S       "         19.75     "       19.67                                      ______________________________________                                    

IR SPECTRUM: NH₂ band 1.580 cm⁻¹ ; OH bands 1.037 cm⁻¹ and 1.350 cm⁻¹ .

    ______________________________________                                         NMR SPECTRUM - Reference TMS                                                   CH.sub.2 OH     3.55 p.p.m. (m)                                                 ##STR19##      2.9 p.p.m. (m)                                                 CH.sub.2S       2.55 p.p.m. (m)                                                4 (CH.sub.2).sub.6                                                                             1.4 p.p.m. (m)                                                 T.L.C.                                                                               Prepared silica gel plates 60F254;                                             H = 8 cm                                                                 Propanol   60                                                                  NH.sub.4 OH                                                                               30                                                                  Ethylene Diamine                                                                          10                                                                  Developers: ninhydrin - I.sub.2                                                ______________________________________                                    

example 5 2,17-diamino-4,15-dithia-1,18-octadecanediol ##STR20##

The operational method of Example 4 is used.

Melting Point: 102° to 104° (Tottoli).

Yield: 52%.

    ______________________________________                                         Analysis for C.sub.16 H.sub.36 O.sub.2 N.sub.2 S.sub.2 = 352.60                ______________________________________                                         C%      calculated                                                                               54.50     found   54.57                                      H       "         10.29     "       10.65                                      N       "         7.94      "       8.20                                       S       "         18.18     "       18.21                                      ______________________________________                                    

IR SPECTRUM: NH₂ band 1577 cm⁻¹ ; OH Bands 1040 cm⁻¹, 1550 cm⁻¹ .

    ______________________________________                                         NMR SPECTRUM - Reference TMS                                                   CH.sub.2 OH     3.55 p.p.m. (m)                                                 ##STR21##      2.9 p.p.m. (m)                                                 CH.sub.2SCH.sub.2                                                                              2.55 p.p.m. (m)                                                (CH.sub.2).sub.8                                                                               1.35 p.p.m. (m)                                                T.L.C.                                                                               Prepared silica gel playtes 60F254                                             H = 8 cm                                                                 Propanol   60                                                                  NH.sub.4 OH                                                                               30                                                                  Ethylene Diamine                                                                          10                                                                  Developers: ninhydrin - I.sub.2                                                ______________________________________                                    

example 6 2,7-diamino-4,5-dithia-1,8-octanediol (Cystinol) ##STR22## (a) CYSTEINOL

500 cm³ of liquefied NH₃ are introduced into a 1000 cm³ three necked flask provided with a sealed mechanical stirrer and a KOH guard.

15 g of S-benzylcysteinol are added and little by little 3.51 g of sodium in fine flakes (excess: 0.13 g in order that the blue coloration persists).

The excess of sodium and the sodium mercaptide of cysteinol are destroyed by 7.4 g of NH₄ Cl.

The ammonia is removed under a nitrogen current and then under high vacuum. The white residue, solid, is not purified.

(b) CYSTINOL (Described in the form of the dihydro chloride by J. C. Crawall et al., J. Chem. Soc. 4066-68 (1956) )

The preceding white residue is taken up by 400 cm³ of distilled water and 1.5 g FeCl₃. A current of air is made to bubble through the solution obtained until the dissappearance of the thiol (sodium nitroprussiate test) which took several hours. The solution is filtered. The colourless filtrate is concentrated under vacuum to 75 cm³, then passed through a column of activated Dowex 50 × 8. The product is eluted with IN NH₄ OH.

The ammoniacal eluants are evaporated under vacuum and the residue, taken up in 100 cm³ of ether, is refluxed. Insolubles are dried under vacuum.

Yield: 83% -- Melting Point: 71° to 73° (Tottoli) White crystals soluble in water, methanol, ethanol.

    ______________________________________                                         Analysis for C.sub.6 H.sub.16 O.sub.2 N.sub.2 S.sub.2 = 212.33                 ______________________________________                                         C%     calculated 33.94    found   34.02 to 34.29                              H      "          7.59     7.78                                                N      "          13.19    "       13.05 to 13.05                              S      "          30.20    "       30.10                                       ______________________________________                                    

IR SPECTRUM: NH₂ band 1605 cm⁻¹ ; OH band 1074 - 1053 cm⁻¹ .

    ______________________________________                                         T.L.C.:                                                                              Prepard silica gel plates 60F254;                                              H = 8 cm                                                                 n-Propanol 60                                                                  NH.sub.4 OH                                                                               30                                                                  Ethylene Diamine                                                                          10                                                                  Developers: Ninhydrin - I.sub.2                                                NMR SPECTRUM - Reference TMS                                                   CH.sub.2 OH     3.55 p.p.m. (m)                                                 ##STR23##      3.15 p.p.m. (m)                                                CH.sub.2S       2.8 p.p.m. (m)                                                 ______________________________________                                    

EXAMPLE 7 Neutral Oxalate of 2,9-diamino-5,6-dithia-1,10-decanediol (homocystinol) ##STR24##

To a solution of 5.3 g of S-benzylhomocysteinol in 250 ml of liquefied ammonia, there is added with mechanical stirring lg (the theoretical amount) of sodium as fine flakes. The ammonia is evaporated at the laboratory temperature to two-thirds and the reaction mixture is treated with 2.67 g of NH₄ Cl added in small amounts, then evaporated.

The residue is taken up by 130 ml of water and 0.5 g of FeCl₃. Air is rapidly made to bubble through it for 5 hours. The thiol is then negative (nitroprussiate test).

The solution is passed over a 100 ml column of activated Dowex 50 × 8 (H = 70 cm, φ = 2 cm). The product is eluted by 2N ammonia and the eluate reduced to dryness.

The residual oil is solidified in ethyl acetate and the resulting powder brought for 15 minutes to reflux in ether then dried. Crude yield = 98%.

The compound is salified by the theoretical quantity of oxalic acid in an alcoholic medium.

The salt is purified by dissolving in the minimum quantity of water and the addition of ethanol up to the commencement of precipitation.

Yield : 35% -- Melting Point : 205° to 207° (Tottoli).

    ______________________________________                                         Analysis for C.sub.10 H.sub.22 O.sub.6 N.sub.2 S.sub.2 = 330.42                ______________________________________                                         C%      calculated                                                                               36.35     found   36.18                                      H       "         6.71      "       6.85                                       N       "         8.48      "       8.47                                       S       "         19.41     "       19.72                                      ______________________________________                                    

IR SPECTRUM : --COO-- band 1575 cm⁻¹ ; OH band 1060 cm⁻¹.

    ______________________________________                                         NMR SPECTRUM - Reference TMS                                                   CH.sub.2CH.sub.2CH                                                                             2.1 p.p.m. (massive)                                           SCH.sub.2CH.sub.2                                                                              2.8 p.p.m. (massive)                                            ##STR25##       3.3 3.9 p.p.m. (massive)                                      T.L.C.                                                                               Prepared silica gel plates 60F254                                              H = 8 cm                                                                 Propanol   60                                                                  NH.sub.4 OH                                                                               30                                                                  Ethylene Diamine                                                                          10                                                                  Developers - Ninhydrin - I.sub.2                                               ______________________________________                                    

example 8 neutral oxalate of 2,10-diamino-5,7-dithia-1,11 undecanediol (homodjenkolol) ##STR26##

To a solution of 10.5 g of S-benzylhomocysteinol in 500 ml liquefield ammonia there is added with stirring 2.3 g of sodium as flakes (the theoretical amount) then the theoretical quantity of dibromo methane (4.35 g). The blockage of the thiol is immediate. The excess of sodium amide is destroyed by 2.67 g of NH₄ Cl and the ammonia evaporated.

The residue is taken up by 200 ml of ether. Insolubles are extracted by 3 × 100 ml of ethyl acetate under reflux with stirring. The ethyl acetate solutions deposited 3.8 g (yield = 60%) crystals.

The product is salified in the form of the oxalate in absolute ethanol. It is purified by dissolving in the minimum of water and re-precipitation by ethanol. After 12 hours in an ice-box, 4.8 g of white crystals are collected.

Yield 56.8%.

Melting Point : 189°-190° (Tottoli) Soluble in water and alcohols.

    ______________________________________                                         Analysis for C.sub.11 H.sub.24 O.sub.6 N.sub.2 S.sub.2 = 344.45                ______________________________________                                         C%      calculated                                                                               38.36     found   38.08                                      H       "         7.02      "       7.10                                       N       "         8.13      "       8.23                                       S       "         18.62     "       18.28                                      ______________________________________                                    

IR SPECTRUM : --COOH band:1580 cm⁻¹ ; OH bands:1073 cm⁻¹, 1300 cm⁻¹.

    ______________________________________                                         NMR SPECTRUM - Reference TMS                                                   SCH.sub.2S      3.82 p.p.m. (s)                                                 ##STR27##                                                                     SCH.sub.2CH.sub.2                                                                              2.8 p.p.m. (m)                                                  ##STR28##      2 p.p.m. (massive)                                             T.L.C.                                                                               (silica gel prepared plates 60F354                                             H = 8 cm)                                                                Propanol   60                                                                  NH.sub.4 OH                                                                               30                                                                  Ethylene Diamine                                                                          10                                                                  Developers: Ninhydrin - I.sub.2                                                ______________________________________                                    

example 9 neutral oxalate of 2,11-diamino-5,8-dithia-1,12 dodecanediol ##STR29##

The operative procedure of Example 8 is followed using double the theoretical quantity of dibromo methane. The blocking time of the thiol is 7 hours. After passage over a column of Dowex 50 × 8, the crude yield is 86%. The yield of purified neutral oxalate is 40%. The white crystals obtained are soluble in water and alcohols.

Melting Point 194°-195.5° (d) (Tottoli).

    ______________________________________                                         Analysis for C.sub.12 H.sub.26 O.sub.6 N.sub.2 S.sub.2 = 358                   ______________________________________                                         C%      calculated                                                                               40.20     found   39.94                                      H       "         7.31      "       7.52                                       N       "         7.81      "       8.15                                       S       "         17.89     "       17.71                                      ______________________________________                                    

IR SPECTRUM : --COOH band:1626 cm⁻¹ ; OH bands:1060 cm⁻¹ and 1300 cm⁻¹.

    ______________________________________                                         NMK SPECTRUM - Reference                                                        ##STR30##       3.4 to 3.9 p.p.m. (massive)                                   S(CH.sub.2).sub.2S                                                                             2.83 p.p.m. (s)                                                SCH.sub.2CH.sub.2                                                                              2.7 p.p.m. (m)                                                  ##STR31##      2 p.p.m. (massive)                                             T.L.C.                                                                               Prepared silica gel plates 60F254                                              H = 8 cm                                                                 Propanol   60                                                                  NH.sub.4 OH                                                                               30                                                                  Ethylene Diamine                                                                          10                                                                  Developers: Ninhydrin - I.sub.2                                                ______________________________________                                    

example 10 mandelate of 2,13-diamino-5,10-dithia-1,14-tetradecanediol ##STR32##

Following always the same operative procedure using the theoretical quantity of 1,4-dibromo-butane, the blockage of the SH groups is obtained in 15 minutes. After extraction by dichloromethane and recrystallisation in ethyl acetate the yield of the impure base is 45%.

The base is salified in ethanol and the neutral mandelate obtained washed with ether. The white crystals obtained are soluble in water, alcohols and dimethylformamide.

M.Pt. 153° (Tottoli) -- Yield : 29%.

    ______________________________________                                         Analysis for C.sub.28 H.sub.44 O.sub.8 N.sub.2 S.sub.2 = 600.79                ______________________________________                                         C%      calculated                                                                               55.97     found   56.26                                      H       "         7.38      "       7.66                                       N       "         4.66      "       4.58                                       S       "         10.67     "       10.93                                      ______________________________________                                    

IR SPECTRUM - --COOH band:1577 cm⁻¹ ; OH bands:1064 cm⁻¹, 1355 cm⁻¹.

    ______________________________________                                         NMR SPECTRUM - Reference TMS                                                    ##STR33##      7.4 p.p.m. (s)                                                  ##STR34##      4.95 p.p.m. (s)                                                CH.sub.2 OH     3.6 p.p.m. (m)                                                  ##STR35##      3.3 p.p.m (massive)                                            CH.sub.2SCH.sub.2                                                                              2.5. p.p.m. (massive)                                           ##STR36##       1.5 to 2 p.p.m.(massive)                                      T.L.C.                                                                               Prepared silica gel plates 60F254                                              H = 8 cm                                                                 Propanol   60                                                                  NH.sub.4 OH                                                                               30                                                                  Ethylene Diamine                                                                          10                                                                  Developers: Ninhydrin - I.sub.2                                                ______________________________________                                    

example 11 mandelate of 2,14-diamino-5,11-dithia-1,15-pentadecanediol ##STR37##

Following the operative procedure of Example 8, an excess of 5% over the theoretical quantity of 1,5-dibromopentane is used. The blockage time of the SH-group is 5 hours. Extraction is carried out by dichloromethane and the product recrystallised in ethyl acetate. The yield of impure base is 63%. The mandelate is prepared in ethanol and washed with ether.

Yield : 49.5% -- M.Pt. : 131°-132° C. (Tottoli) Soluble in water, alcohols, DMF.

    ______________________________________                                         Analysis for C.sub.29 H.sub.46 O.sub.8 N.sub.2 S.sub.2 = 614.82                ______________________________________                                         C%      calculated                                                                               56.65     found   56.81                                      H       "         7.54      "       7.75                                       N       "         4.55      "       4.64                                       S       "         10.43     "       10.38                                      ______________________________________                                    

IR SPECTRUM : --COOH band : 1587 cm⁻¹ . OH bands : 1064 cm⁻¹, 1351 cm⁻¹.

    ______________________________________                                         NMR SPECTRUM: Reference TMS                                                     ##STR38##      7.4 p.p.m. (s)                                                  ##STR39##      4.95 p.p.m. (s)                                                CH.sub.2 OH     3.6 p.p.m. (massive)                                            ##STR40##      3.3 p.p.m. (massive)                                           CH.sub.2SCH.sub.2                                                                              2.5 p.p.m. (massive)                                            ##STR41##       1.3 to 2 p.p.m. (massive)                                     T.L.C. Prepared plates 60F254 H = 8 cm                                         Propanol   60                                                                  NH.sub.4 OH                                                                               30                                                                  Ethylene diamine                                                                          10                                                                  Developers: Ninhydrin -I.sub.2                                                 ______________________________________                                    

example 12 2,15-diamino-5,12-dithia-1,16-hexadecanediol ##STR42##

Following the operative procedure of Example 8 there is obtained, using the theoretical quantity of 1,6-dibromohexane, a thiol blockage time of 15 minutes. After extraction by dichloromethane and recrystallisation in ethyl acetate white crystals are obtained.

M.Pt. : 79°-81° (Kofler) -- Yield : 61%. White crystals soluble in water and alcohols.

    ______________________________________                                         Analysis for C.sub.14 H.sub.32 O.sub.2 N.sub.2 S.sub.2 = 324.55                ______________________________________                                         C%     calculated 51.81    found   51.80 - 51.52                               H      "          9.44     "       10.23 - 10.30                               N      "          8.63     "       8.67                                        S      "          19.76    "       19.52                                       ______________________________________                                    

IR SPECTRUM : NH₂ band : 1550 cm⁻¹ ; OH bands : 1060 cm⁻¹, 1350 cm⁻¹.

    ______________________________________                                         NMR SPECTRUM - Reference TMS                                                    ##STR43##      1.6 p.p.m. (massive)                                           2CH.sub.2 OH    3.5 p.p.m. (m)                                                 4CH.sub.2S      2.6 p.p.m. (m)                                                  ##STR44##      3 p.p.m. (massive)                                             T.L.C.                                                                               Prepared plates 60F 254 H = 8 cm                                         n-Butanol       40                                                             Ethylene diamine                                                                               50                                                             Acetic acid     10                                                             Developers: Ninhydrin -I.sub.2                                                 ______________________________________                                    

example 13 2,17-diamino-5,14-dithia-1,18-octadecanediol ##STR45##

Following the operative procedure of Example 8 there is obtained using the theoretical quantity of 1,8-dibromo-octane blockage of the thiol in one hour. Extraction is carried out by dichloromethane and recrystallisation in ethyl acetate.

M.Pt. : 84° C. (Kolfer) -- Yield : 28% White crystals soluble in water and alcohols.

    ______________________________________                                         Analysis for C.sub.16 H.sub.36 O.sub.2 N.sub.2 S.sub.2 = 352.6                 ______________________________________                                         C%      calculated                                                                               54.50     found   54.42                                      H       "         10.29     "       10.42                                      N       "         7.94      "       7.87                                       S       "         18.18     "       17.95                                      ______________________________________                                    

IR SPECTRUM : NH₂ band: 1560 cm⁻¹ ; OH bands: 1064 cm⁻¹, 1345 cm⁻¹.

    ______________________________________                                         NMR SPECTRUM                                                                    ##STR46##      1.6 p.p.m. (massive)                                           2-CH.sub.2OH    3.5 p.p.m. (m)                                                 4-CH.sub.2S     2.6 p.p.m. (m)                                                  ##STR47##      3 p.p.m. (massive)                                             T.L.C.                                                                               Prepared plates 60F 254 H = 8 cm                                         Propanol        60                                                             NH.sub.4 OH     30                                                             Ethylene diamine                                                                               10                                                             Developers: Ninhydrin -I.sub.2                                                 ______________________________________                                    

example 14 2,19-diamino-5,16-dithia-1,20-eicosanediol ##STR48##

Following the operative procedure of Example 8 and using an excess of 20% relative to the theoretical quantity of 1,10-dibromo-decane, the blockage of the thiol is effected in 2 hours 30 minutes. The product is extracted with dichloromethane and recrystallised in ethyl acetate.

Yield : 27% -- White crystals soluble in water and alcohols.

    ______________________________________                                         Analysis for C.sub.18 H.sub.40 O.sub.2 N.sub.2 S.sub.2 = 380.59                ______________________________________                                         C%      calculated                                                                               56.79     found   56.87                                      H       "         10.59     "       10.71                                      N       "         7.36      "       7.07                                       S       "         16.85     "       16.76                                      ______________________________________                                    

IR SPECTRUM NH₂ band : 1550 cm⁻¹ ; OH bands : 1060 cm⁻¹ - 1350 cm⁻¹ .

    ______________________________________                                         NMR SPECTRUM                                                                    ##STR49##       1.5 p.p.m. (massive) -4-CH.sub.2S 2.6 p.p.m. (m)              2-CH.sub.2 OH   3.4 p.pm. (m)                                                   ##STR50##      2.9 p.p.m. (massive)                                           T.L.C.                                                                               Prepared plates 60F 254 H = 8 cm                                         Propanol        60                                                             NH.sub.4 OH     30                                                             Ethylene diamine 10                                                            Developers: Ninhydrin -I.sub.2                                                 ______________________________________                                    

pharmacological Study

The compounds of the invention were subjected to various tests with a view to determining their therapeutic activity.

TOXICITY

The products of the invention are hardly toxic.

The oral LD 50 (see the table below) was determined according to the method of Karber and Behrens (Arch. Exp. Pathol. Pharm. 177, 1935, page 379) on mice EVIC CEBA ♀ Swiss EOPS NMRI Han of 24 to 26 g weight.

The results are given in the table below.

HYPOLIPEMIC : HYPERLIPIDEMIC ACTIVITY EXPERIMENTALLY INDUCED BY TRITON

The compounds of the invention possess useful hypolipemic properties.

The technique used to show these properties has been described by M. Friedman and S. E. Byers in : J. Exptl. Med. 97, 117, 1953 and likewise by S. Garattini and colleagues in Arzneim. Forsch. 9, 206, 1959.

The rats received intravenously 0.3 ml per 100 grams of body weight of a solution of Triton 13 39 at 10%. The products to be tested are administered simultaneously orally at a dose corresponding to a tenth of their LD 50, determined orally in mice, without the dose used exceeding 500 mg/kg.

Eighteen hours after the injection of Triton the animals are sacrificed by section of the carotid and the blood is collected to determined the lipid parameters : cholesterol (auto-analyser Technicon AA II Lieberman Burchard), beta- lipoproteins, (Burnstein), total lipids (Chabrol and Charonnat), triglycerides (Boehringer enzymatic).

The optical density of the serum at 691 nanometres is measured in each case. Each product was tested on ten animals. The statistic calculations were carried out on the averages affected by their divergence from the average using the Student test.

The reference compound used is clofibrate.

The table below sets out the results obtained.

                                      TABLE                                        __________________________________________________________________________               Hypolipemic activity                                                 LD 50           percentages of diminution                                            g/kg                                                                               Dose        β-lipopro-                                                                      total        optical                               Compound                                                                             per os                                                                             mg/kg p.o.                                                                           Cholesterol                                                                          tein  lipids                                                                               Triglycerides                                                                         serum density                         __________________________________________________________________________     Clofibrate                                                                           2,3 225   28    36    26    25                                                           p ≦ 0.001                                                                     p ≦ 0.01                                                                      p ≦ 0.001                                                                     p ≦ 0.001                                                                      --                                    Example 1                                                                            > 5 500   10    NS    NS    NS     NS                                                    p ≦ 0.05                                                Example 2                                                                            5   500   NS    NS    NS    14     NS                                                                      p ≦ 0.05                              Example 3                                                                            2.7 270   4     39    27    28     53                                                    NS    p ≦ 0.01                                                                      p ≦ 0.001                                                                     p ≦ 0.001                                                                      p ≦ 0.01                       Example 4                                                                            1.275                                                                              127   10    24    NS    34     57                                                    p ≦ 0.01                                                                      p ≦ 0.01                                                                            p ≦ 0.001                                                                      p ≦ 0.001                      Example 5                                                                            1.75                                                                               175   8     NS    NS    30     56                                                    p ≦ 0.02   p ≦ 0.01                                                                       p ≦ 0.01                       Example 6                                                                            3.1 310   40    46    38    42     78                                                    p ≦ 0.0001                                                                    p ≦ 0.0001                                                                    p ≦ 0.001                                                                     p ≦ 0.0001                                                                     p ≦  0.0001                    Example 12                                                                           2.5 250   NS    11    NS    NS     NS                                                          p ≦ 0.01                                          Example 13                                                                           1.4 140   13    23    27    33     48                                                    p ≦ 0.02                                                                      p ≦ 0.001                                                                     p ≦ 0.01                                                                      p ≦ 0.01                                                                       p ≦ 0.05                       Example 14                                                                           0.95                                                                                95   NS    15    NS    NS     NS                                                          p ≦ 0.001                                         __________________________________________________________________________      NS : non-significant result                                              

These compounds which can be administered orally are suggested for use in the treatment of lipid disturbances isolated or associated with atherosclerotic symptoms such as hypercholesterolemias, hypertriglyceridemias and mixed hyperlipidemias. The therapeutic indications tend to myocardial coronary infarctus, insufficient cerebral vasculation, arteritis of the lower members, arterial hypertension etc.

The dose of the compounds of the invention is of the order of 0.3 g to 2 g of active substance per day, i.e. 5 to 30 mg/kg per day.

The compound of the invention can be administered in various pharmaceutical forms such as tablets, dragees capsules, granules etc.

Examples of pharmaceutical compositions are given below:

    ______________________________________                                         Lozenges :                                                                     Compound of Example 6   250 mg                                                 Colloidal silica        20 mg                                                  Talc                    15 mg                                                  Tablets :                                                                      Compound of Example 6   500 mg                                                 Colloidal silica        20 mg                                                  Microcrystalline cellulose                                                                             50 mg                                                  Lactose                 50 mg                                                  Magnesium stearate      10 mg                                                  ______________________________________                                     

We claim:
 1. A pharmaceutical composition useful in the treatment of lipid disturbances which comprises, as active ingredient a hypolipemic amount of, a compound corresponding to the general formula I ##STR51## in which n is equal to 0 or represents a whole number from 1 to 10 and m represents the number 1 or 2 or a pharmacologically acceptable salt of such a compound, together with a pharmacologically acceptable carrier or diluent.
 2. A pharmaceutical composition according to claim 1 wherein the ctive ingredient is selected from the group consisting of:2,8-diamino-4,6-dithia-1,9-nonanediol, 2,11-diamino-4,9-dithia-1,12-dodecanediol, 2,13-diamino-4,11-dithia-1,14-tetradecanediol, 2,15-diamino-4,13-dithia-1,16-hexadecanediol, 2,17-diamino-4,15-dithia-1,18-octadecanediol, 2,7-diamino-4,5-dithia-1,8-octanediol, 2,15-diamino-5,12-dithia-1,16-hexadecanediol, 2,17-diamino-5,14-dithia-1,18-octadecanediol, 2,19-diamino-5,16-dithia-1,20-eicosanediol, and their pharmacologically acceptable salts
 3. A pharmaceutical composition according to claim 1 which is in an orally administrable form.
 4. A pharmaceutical composition according to claim 3 which is in a form permitting administration of doses of from 5 to 30 mg/kg per day.
 5. A method of treating a human patient afflicted with a lipid disturbance which method comprises administering to the patient a hypolipemic amount of a compound of formula I ##STR52## in which n is equal to 0 or represents a whole number from 1 to 10 and m represents the number 1 or 2 or a pharmacologically acceptable salt thereof.
 6. The method of claim 5, wherein the compound is selected from the Group consisting of:2,8-diamino-4,6-dithia-1,9-nonanediol, 2,11-diamino-4,9-dithia-1,12-dodecanediol, 2,13-diamino-4,11-dithia-1,14-tetradecanediol, 2,15-diamino-4,13-dithia-1,16-hexadecanediol, 2,17-diamino-4,15-dithia-1,18-octadecanediol, 2,7-diamino-4,5-dithia-1,8-octanediol, 2,15-diamino-5,12-dithia-1,16-hexadecanediol, 2,17-diamino-5,14-dithia-1,18-octadecanediol, 2,19-diamino-5,16-dithia-1,20-eicosanediol, and their pharmacologically acceptable salts.
 7. The method of claim 5, wherein the compound is administered orally.
 8. The method of claim 7, wherein the compound is administered in a dose of five to thirty mg/kg per day. 